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Appendix C: Methylene Blue and Serotonin Syndrome From: Perioperative Medication Management – Adult/Pediatric – Inpatient/Ambulatory Clinical Practice Guideline Last Reviewed 2/2020; Last Updated 6/2019 Contact information: Philip J. Trapskin, PharmD, Phone Number: (608) 263-1328, [email protected]

Summary: Although the exact mechanism of this drug interaction is unknown, methylene blue inhibits the action of monoamine oxidase A - an enzyme responsible for breaking down serotonin in the brain. It is believed that when methylene blue is given to patients taking serotonergic psychiatric medications, high levels of serotonin can build up in the brain, causing toxicity. See Table 1. Psychiatric medications with serotonergic activity. • In emergency situations requiring life-threatening or urgent treatment with methylene blue (as described above), the availability of alternative interventions should be considered and the benefit of methylene blue treatment should be weighed against the risk of serotonin toxicity. If methylene blue must be administered to a patient receiving a serotonergic drug, the serotonergic drug must be immediately stopped, and the patient should be closely monitored for emergent symptoms of CNS toxicity for two weeks (five weeks if fluoxetine [Prozac] was taken), or until 24 hours after the last dose of methylene blue, whichever comes first. • In non-emergency situations when non-urgent treatment with methylene blue is contemplated and planned, the serotonergic psychiatric medication should be stopped to allow its activity in the brain to dissipate. Most serotonergic psychiatric drugs should be stopped at least 2 weeks in advance of methylene blue treatment. Fluoxetine (Prozac), which has a longer half-life compared to similar drugs, should be stopped at least 5 weeks in advance • Possible signs/symptoms of Serotonin Syndrome: mental status changes, muscle twitching, excessive sweating, shivering or shaking, diarrhea, ataxia, fever • Treatment with the serotonergic psychiatric medication may be resumed 24 hours after the last dose of methylene blue • Serotonergic psychiatric medications should not be started in a patient receiving methylene blue. Wait until 24 hours after the last dose of methylene blue before starting the antidepressant.

References: 1. FDA Drug Safety Communication. http://www.fda.gov/Drugs/DrugSafety/ucm263190.htm#Hcp. Updated 10/20/2011. 2. Bach KK, Lindsay FW, Berg LS, Howard RS. Prolonged postoperative disorientation after methylene blue infusion during parathyroidectomy. Anesth Analg. 2004;99:1573-4. 3. Kartha SS, Chacko CE, Bumpous JM, Fleming M, Lentsch EJ, Flynn MB. Toxic metabolic encephalopathy after parathyroidectomy with methylene blue localization. Otolaryngol Head Neck Surg. 2006;135:765-8.

Copyright © 2020 University of Wisconsin Hospitals and Clinics Authority. All Rights Reserved. Printed with Permission. Contact: [email protected] Vermeulen, [email protected] Last Revised: 04/2020 Effective 4/6/2020. Contact [email protected] for previous versions.

Table 1. Psychiatric medications with serotonergic activity Generic name Found in Brand name(s) Selective Serotonin Reuptake Inhibitors (SSRIs) paroxetine Paxil, Paxil CR, Pexeva fluvoxamine Luvox, Luvox CR fluoxetine Prozac, Sarafem, Symbyax sertraline Zoloft citalopram Celexa escitalopram Lexapro Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs) venlafaxine Effexor, Effexor XR desvenlafaxine Pristiq duloxetine Cymbalta Tricyclic Antidepressants (TCAs) amitriptyline Amitid, Amitril, Elavil, Endep, Etrafon, Limbitrol, Triavil desipramine Norpramin, Pertofrane clomipramine Anafranil imipramine Tofranil, Tofranil PM, Janimine, Pramine, Presamine nortriptyline Pamelor, Aventyl hydrochloride protriptyline Vivactil doxepin Sinequan, Zonalon, Silenor trimipramine Surmontil Monoamine Oxidase Inhibitors (MAOIs) isocarboxazid Marplan phenelzine Nardil selegiline Emsam, Eldepryl, Zelapar tranylcypromine Parnate Other Psychiatric Medications amoxapine Asendin maprotiline Ludiomil nefazodone Serzone trazodone Desyrel, Oleptro, Trialodine bupropion Wellbutrin, Wellbutrin SR, Wellbutrin XL, Zyban, Aplenzin buspirone Buspar vilazodone Viibryd mirtazapine Remeron, Remeron Soltab

Copyright © 2020 University of Wisconsin Hospitals and Clinics Authority. All Rights Reserved. Printed with Permission. Contact: [email protected] Vermeulen, [email protected] Last Revised: 04/2020